Todd E. Golde, M.D., Ph.D., is executive director of the Evelyn F. and William L. McKnight Brain Institute of the University of Florida. He oversees neuroscience and neuromedicine research programs across the University of Florida campus. A professor of neuroscience and neurology, Dr. Golde joined the University of Florida faculty in 2009 and became founding director of the university’s Center for Translational Research in Neurodegenerative Disease, which he led until taking charge of the McKnight Brain Institute in December 2016. He is also director of the NIH funded 1Florida Alzheimer’s disease Research Center group of institutions.

An internationally known expert in the scientific understanding of Alzheimer’s disease, Dr. Golde has published more than 240 papers that have been cited more than 30,000 times, (https://scholar.google.com/citations?user=X_9xacsAAAAJ&hl=en), and has expanded his leading-edge research to include other neurodegenerative diseases, cancer and even malaria. He is lead investigator for the Facial Pain Research Foundation’s Gene Therapy Research Project, at the University of Florida, to find the cures for TN.

Dr. Golde spoke with Mervyn Rothstein, who was a writer and editor at The New York Times for nearly 30 years and now writes the Stage Directions column – a series of interviews with theater directors – for Playbill.com. His first symptoms of trigeminal neuralgia occurred in 2005.

How and why did you become Involved In the “World” Of Scientific Research?

TG: I’ve loved biology from as far back as I can remember. The real catalyst was when I was in my junior year in college. I didn’t know what I was going to do. I was thinking about going back and teaching at a boarding school for a while before I figured out what I was going to do with my life. But I was a biology major at Amherst College and I took a course with a professor named Richard Goldsby, a wonderful teacher, who was basically teaching a graduate level course to undergraduates. We had to write a term paper, a research-hypothesis type paper, the first time I’d had to do that in college, and the response back was that this was one of the best papers he’d read in many years, undergraduate or graduate. Please come talk to me. I think you might like to do research.

Your laboratory conducts disease oriented research with specific, but not exclusive focus on neurodegenerative diseases such as Alzheimer’s disease and Parkinson’s disease. How did you get involved in developing a research project to find a cure for Trigeminal Neuralgia and related neuropathic pain?How did the development of this research project come about, and what motivated you to take on the leadership role?

TG: I make no claims about being a facial pain or trigeminal neuralgia expert. I’m just thinking opportunistically about how we can make a difference. When I came to the University of Florida, I was the founding director of the Center for Translational Research in Neurodegenerative Disease. The chair of the department of neurology at that time had hired somebody named Dr. Andy Ahn. Andy worked on headache and pain, and the director needed a place for him. I had some space at that time, so Andy was a scientific neighbor, and we would have discussions.

The University of Florida is one of the hotbeds in the world in terms of a gene therapy approach based on adeno-associated viral vectors – we call it AAV for short. A former dean actually discovered this virus. One of our senior faculty members participated in creating the first gene therapy vectors around it. My lab had already been using AAV vectors, but we doubled or tripled down when we came to the University of Florida. AAV has a naturally affinity to get into neurons.

So Andy sort of triggered this, but my bandwidth was stretched at that point – it’s still stretched. I kept on tweaking Andy to go down this road. Andy left academics, and at some point I said I should do this.

We felt it could be something that could be rapidly translatable. Finding a cure for trigeminal neuralgia is a huge unmet medical need, but it’s an orphan disease that doesn’t affect enough people to attract a huge amount of attention.

There’s a chance for harm if we get into humans, but the nice thing about working with trigeminal neuralgia is we can at least start our initial studies in humans in people whose next option is surgical ablation of the trigeminal nerve. That means that there’s an out if we actually happen to make people worse. When we do these kinds of trailblazing experiments or envision them in humans, we need to make sure that if something could go wrong we have a way out.

Now we’ll begin the animal phase of study – testing in animals. And I know how much this research can really affect people’s lives. It may not work, but we have everything in place to test it. So let’s try.

If Gene Therapy isn’t new, why do you believe that it can work to block pain signaling in the nerve?

TG: It really comes down to technical details. People have used the wrong vectors before that had their own liabilities. I honestly just don’t think people have thought that much about this approach.

Last year, gene therapy had its first really radical major success outside of the eye, which was with children who had a disease called spinal muscular atrophy (SMA). They were treated systemically with a AAV vector – a different flavor of the same thing. These kids basically get spinal motor neuron degeneration when they’re young, by the time they’re two years old, typically, they die. Fifteen children were treated with huge amounts of virus, and reports last October showed that every one of these kids was alive at two years of age. And those with high-dose vectors, many of them were almost asymptomatic. At that age the expected survival rate would have been eight percent. So there are some children walking and living normal lives after gene therapy who otherwise would be most likely dead.

So I think that was a turning point in the field, to say this, AAV-based gene therapies, really will have its place in modern medicine. And that study in SMA was much more heroic and much more challenging than what we envision. So I think the time’s right. We know we can deliver the gene to the nerve. So now it’s just finding the right gene that will dampen pain signaling in that set of neurons, hopefully without doing harm.

Supposing your theory and project is proven successful. What implications or lessons wil this work provide for other researchers?

TG: I think it would say that perhaps the gloves come off on gene therapies for many disorders, especially things that are targeting nerve cell dysfunction.

Because of the Hippocratic Oath – physician, do no harm – we need an out, so we wouldn’t want to go and do this on intractable sciatic nerve pain. Because what happens if you make them worse – you can’t cut their sciatic nerve without serious implications.

But I think success could open up the door to many different approaches targeting pain. And given the current opioid epidemic, driven from people at least initially taking these medications to treat chronic pain – (whether that’s right or wrong or medically appropriate is another question) – I think this viral approach enables us to deliver the medicine or treatment precisely to the cells or organ or nerve and hopefully avoid the systemic side effects that would come from taking a pill or an antibody or other approaches.

And ultimately, I think it could also be relatively affordable. We’re jubilant about a medical success when a new treatment comes out for a previously incurable or untreatable disorder, especially when it shows a huge impact – for instance, something that saves somebody from a cancer that was previously untreatable. And then you dig in and find what the price tag of that therapy is and you go oh, my God, can we afford that as a society? So you never know – I wouldn’t be the person to set a price if we potentially have a therapy for this – but at least the development cost associated with this could be dramatically lower than development costs typically for current small-molecule therapies or for current biologic therapies like antibodies.

For getting to a phase one trial for initial proof of concept in man, often just the investment is $30 million or $50 million, just for the goods, to make enough of the drug and have the safety testing of it. We think we could probably do this now for $5 million or $10 million, but I expect that cost, especially for very limited diseases, to come down much lower in the future. And that would be transformative.

The final thing is that pretty much the therapy that we find in the laboratory, we might tweak it a little bit along the way as we move it toward a human study, but it’s pretty much the same as we would use in a human. Often that’s not the case with any other type of therapies – what I do in a mouse model, for example, has to be tweaked so much. I think this would be a huge advantage.

When do you envision (or hope) that gene therapy treatments for neuropathic pain {including Trigeminal Neuralgia) will be ready for use in humans?

TG: I think we have about a year to find out whether we can make a go/no go decision in our animal models. If everything goes well, it’s reasonable to say that will be about a year.

Then there are a whole lot of factors that will go into answering the question “can you take something from a laboratory to get into a human clinical trial?” In the best-case scenario, that would take about a year. That’s if everything aligned. That means you have to have investors, funding, a production method. Two years would be very, very optimistic. Three years would be more realistic.

What are the biggest obstacles you face in translating your preclinical findings to the clinic?

TG: Something untoward that you can’t predict – unexpected toxicities, for example. Also, funding. For less than $200,000 we think we can actually figure out what a lead therapeutic agent might look like – if I and my colleagues have been smart enough to come up with the right thing. Then you take an exponential leap of costs in terms of everything you have to do to get into humans. You’re not going to do that probably in something like this for less than multiple millions of dollars. Many, many agents need tens of millions of dollars to get through what they call the valley of death. And they call it that for a lot of reasons – many things can go wrong. You never know. So it’s just the unknowns. This is pioneering in many ways. There’s not necessarily even F.D.A. guidance for things like this. You’d have to be the trailblazer.

The Facial Pain Research Foundation is moving forward with a sense of urgency to find cures for Trigeminal Neuralgia and related facial pain. Why have you linked your efforts to such a new organization in the field of pain research? And what is the importance of this Trigeminal Research Study and what potential is there for having an impact on the study of other diseases and possible cures?

TG: Well, Michael Pasternak’s a persuasive guy.

We’re doing some really neat science in multiple areas, and I could spend my life doing things that are just neat science. But I’ve always felt that I’d like to see the fruits of my scientific labors actually make a difference for a patient. I think they have in some ways in terms of the mass contribution to our understanding of Alzheimer’s disease and therapies, but I can’t say that that was my therapy that’s actually being used in a patient.

I think maybe it’s a little bit of hubris, but I think we have the right people at the right time sitting around a table with enough resources to address an area of a huge unmet medical need on the individual level. If we can make an impact in a very noninvasive and permanent treatment for trigeminal neuralgia, then perhaps we can expand that in a big way to take on many local pain syndromes using essentially the same methodology.

Every day people in pain are contacting The Facial Pain Research Foundation asking if it is truly possible to find a cure for Trigeminal Neuralgia and related facial pain. How would you respond to their questions? And how can patients in pain help scientists like yourself work toward the cures?

TG: The more people that get engaged, the more people are aware, the better things will be. We have gained a huge amount of knowledge over the years about pain signaling and receptor biology. And one way to help is to philanthropically support us. Benefactors can provide that seed funding that can open up science that’s in the shadows. We’re doing stuff with gene therapy here in terms of a pre-clinical tool or moving it toward therapeutics in cancer or for brain disease, but I hadn’t really thought about applying it for trigeminal neuralgia. Those two have sort of come together, and maybe we’ll take this from science in the shadows to being science right under the streetlight that will now become a common way to move therapies forward for nerve disorders.

Some Trigeminal Neuralgia patients are fearful that we may never find a cure and are fearful to try risky surgeries. What encouraging words do you have for these people?

TG: I think the encouraging words are that what we’re trying here is a very precision-medicine approach. We’re trying to target the molecular pathways of pain signaling very specifically within a nerve so that we can perhaps block that pain signaling, and do so in a minimally invasive way and do so potentially permanently. Will it work on everyone? I can’t guarantee that. But if we can do something where we can reduce pain levels on average 90 percent and we can do so nine times out of ten, I’d take those odds. And I’m pretty confident that we can make an impact. I don’t know how big that impact will be and I don’t know if in the initial versions we can make this as precise as I’d like. But that’s what we’re going to try to address over the next year. Conceptually, this is pretty straightforward. Things can always go wrong. Science can be really humbling. I thought that when we figured out the trigger of Alzheimer’s disease or at least laid the groundwork for what we think is the trigger of Alzheimer’s disease in the early 1990s that we’d be a lot farther along in treating that disease. But that’s not where we’re at.

You are considered an outstanding scientist, Director of UF McKnight Brain Institute. What keeps you awake at night?

TG: I run a big lab. I have multiple collaborators. I have employees dependent on rewards linked to producing successful science. We live hand to mouth every year. We’re dependent on Alzheimer’s funding from the state of Florida. We are dependent on grants to keep the science moving forward and my staff employed. I am tenured, it’s hard to get rid of me, but if we don’t have funding, the team around me might have to find employment elsewhere. That’s what I worry about. We’re always fighting for enough funds to make this happen, and advance our science that might benefit patients in some way.